Mounting evidence suggests that exposure to exogenous estrogens and estrogenic compounds such as selective estrogen receptor modulators (SERMs) and tibolone may increase the risk of stroke in women. Since phytoestrogens, plant-derived estrogens, are known to possess estrogenic effects similar to SERMs and have been marketed as natural and "safe" alternatives to estrogen therapy, significant concerns have been raised as to whether high exposure to phytoestrogens may confer the same risk of stroke. Another intriguing question has also arisen whether endogenous estrogen levels play a role in predicting stroke risk. We propose to address these questions in a prospective cohort of 74,942 adult Chinese women enrolled in the Shanghai Women's Health Study (SWHS) from 1997 to 2000. Specifically, we propose to verify incident stroke cases identified in this cohort during follow-up through medical record review. We will examine the association between dietary intake of soy phytoestrogens and risk of total stroke and stroke subtypes in the full cohort. Repeated dietary measurements will be used for the analyses. In addition, we propose to conduct a nested case-control study among postmenopausal women to investigate the association of ischemic stroke (the predominant type of stroke) with urinary levels of isoflavonoids, a biomarker of systemic exposure to phytoestrogens, and with blood levels of estradiol, estrone, testosterone, and sex hormone- binding globulin. We will include 1500 incident cases of ischemic stroke and 1500 individually matched controls. Isoflavonoids and sex hormones will be measured in biological samples collected at baseline using LC-MS based methods. The SWHS represents an exceptional opportunity to address the targeted questions given its large size, prospective design, high follow-up rates, extensive exposure and disease outcome information collected over the past decade, availability of biological samples, and the unique study population with a high level of soy consumption and low prevalence of hormone therapy use. Results of this proposed study will fill important gaps in our knowledge regarding the role of phytoestrogen and endogenous estrogen exposure in the etiology of stroke in women. PUBLIC HEALTH RELEVANCE: This proposed study is intended to fill important gaps in our knowledge about whether high exposure to plant estrogens (phytoestrogens) and endogenous estrogens in women may raise the risk of stroke, one of the leading causes of death and long-term disability in the United States and many other countries. Study results may contribute to the development of new strategies for the primary prevention of stroke.